History of Peptide Discovery

Overview

The history of peptide therapeutics spans over a century, beginning with the discovery that transformed diabetes from a death sentence into a manageable condition. Each decade has brought new techniques, new compounds, and new understanding of how short chains of amino acids serve as the body's most versatile signaling molecules.

This timeline traces the major milestones in peptide science — from isolation and characterization of endogenous peptides, through the development of synthetic methods that made large-scale production possible, to the modern era of engineered peptides and multi-receptor agonists that have reshaped entire disease categories.

The Insulin Era (1920s–1950s)

1921–1922: The Discovery of Insulin

The isolation of insulin from canine pancreatic extracts by Frederick Banting and Charles Best at the University of Toronto represents the foundational moment in peptide therapeutics. Their work, supported by biochemist James Collip who purified the extract for human use, led to the first successful treatment of a patient with type 1 diabetes in January 1922.

Insulin was the first peptide hormone identified and the first used therapeutically. Its discovery earned Banting and his supervisor John Macleod the Nobel Prize in Physiology or Medicine in 1923.

1951–1953: Sequencing and Structure

Frederick Sanger at Cambridge University determined the complete amino acid sequence of insulin — the first protein ever fully sequenced. This work, completed over several years, demonstrated that proteins have defined, deterministic structures rather than being random amino acid mixtures. Sanger received the Nobel Prize in Chemistry in 1958 for this achievement.

1955: Oxytocin Synthesis

Vincent du Vigneaud synthesized oxytocin, a nine-amino-acid peptide hormone, marking the first chemical synthesis of a polypeptide hormone. This proved that peptides could be made in the laboratory without biological sources and earned du Vigneaud the Nobel Prize in Chemistry in 1955.

The Synthesis Revolution (1960s–1970s)

1963: Solid-Phase Peptide Synthesis

Robert Bruce Merrifield at Rockefeller University developed solid-phase peptide synthesis (SPPS), a method that revolutionized peptide chemistry. By anchoring the growing peptide chain to an insoluble solid support, Merrifield made peptide synthesis faster, more reliable, and amenable to automation. This invention, which earned Merrifield the Nobel Prize in Chemistry in 1984, remains the foundation of modern peptide manufacturing.

1960s–1970s: Endogenous Peptide Discovery Boom

The development of radioimmunoassay (RIA) by Rosalyn Yalow and Solomon Berson enabled the detection and measurement of peptides at extremely low concentrations in biological fluids. This technology, which earned Yalow the Nobel Prize in 1977, catalyzed the discovery of dozens of endogenous peptide hormones:

• Gastrin: Gastrointestinal hormone regulating stomach acid secretion
• Somatostatin: Growth hormone-inhibiting hormone, discovered 1973
• Enkephalins: Endogenous opioid peptides, discovered 1975
• Endorphins: Endogenous morphine-like peptides
• Substance P: Neuropeptide involved in pain and inflammation signaling
• Vasoactive Intestinal Peptide (VIP): Gut-brain signaling peptide

1977: Recombinant Insulin

The advent of recombinant DNA technology enabled production of human insulin in bacteria (E. coli). Genentech and Eli Lilly brought recombinant human insulin to market in 1982, replacing animal-derived insulin and establishing the model for biotechnology-produced peptide drugs.

The Growth Hormone Era (1980s–1990s)

1985: Recombinant Growth Hormone

The withdrawal of cadaver-derived growth hormone (linked to Creutzfeldt-Jakob disease) coincided with the availability of recombinant hGH, produced through biosynthetic methods. This transition demonstrated both the risks of biological-source peptides and the advantages of recombinant production.

1980s–1990s: Growth Hormone Secretagogue Discovery

Research teams identified and characterized the growth hormone secretagogue receptor and developed synthetic compounds that stimulate endogenous GH release:

• GHRP-6: One of the earliest synthetic growth hormone releasing peptides
• GHRP-2: Improved selectivity and potency over GHRP-6
• Hexarelin: Potent GH secretagogue with cardiovascular research applications
• Growth Hormone Releasing Hormone (GHRH) analogs: Including Sermorelin, approved for diagnostic use in 1997

1999: Ghrelin Discovery

Masayasu Kojima and Kenji Kangawa identified ghrelin, the endogenous ligand for the growth hormone secretagogue receptor. This discovery connected appetite regulation, energy homeostasis, and GH secretion through a single peptide signaling system and provided the molecular basis for understanding how GH secretagogues function.

The Incretin Revolution (2000s–2020s)

The GLP-1 Story

The incretin effect — the observation that oral glucose produces a greater insulin response than equivalent intravenous glucose — was recognized in the 1960s. The identification of GLP-1 as the primary incretin hormone in the 1980s by researchers including Joel Habener, Daniel Drucker, and Jens Juul Holst set the stage for one of the most impactful pharmaceutical developments of the 21st century.

Key milestones:

• 2005: Exenatide (Byetta) — The first GLP-1 receptor agonist approved by the FDA, derived from exendin-4, a peptide found in the saliva of the Gila monster lizard
• 2010: Liraglutide (Victoza) — A human GLP-1 analog with a fatty acid modification enabling once-daily dosing
• 2017: Semaglutide (Ozempic) — Further engineered for weekly dosing through albumin-binding modifications. Would later become one of the most prescribed medications globally
• 2019: Oral Semaglutide (Rybelsus) — The first oral GLP-1 receptor agonist, achieved through co-formulation with the absorption enhancer SNAC
• 2022: Tirzepatide (Mounjaro) — The first dual GIP/GLP-1 receptor agonist, demonstrating superior glycemic and weight outcomes
• 2023–2024: Semaglutide for obesity (Wegovy) and Tirzepatide for obesity (Zepbound) — FDA approvals for weight management expanded the market dramatically
• 2024+: Retatrutide — Triple agonist (GIP/GLP-1/Glucagon) entering Phase 3 trials with unprecedented weight loss data

Parallel Developments in Research Peptides

While the pharmaceutical industry developed approved peptide drugs, a parallel stream of research produced compounds that gained significant attention outside traditional clinical development:

BPC-157

Body Protection Compound-157, a synthetic pentadecapeptide derived from human gastric juice, emerged from the research of Predrag Sikiric at the University of Zagreb beginning in the 1990s. Extensive preclinical studies have documented tissue-protective and regenerative properties, though formal clinical trials remain limited.

Thymosin Beta-4 (TB-500)

Originally isolated from thymus tissue, Thymosin Beta-4 was characterized as a 43-amino-acid peptide involved in cell migration and tissue repair. Research by Allan Goldstein and others established its role in wound healing, cardiac repair, and inflammation modulation.

GHK-Cu

The copper-binding tripeptide GHK-Cu was identified by Loren Pickart in the 1970s as a factor in human plasma that promoted tissue repair. Research over subsequent decades revealed roles in collagen synthesis, anti-inflammatory signaling, and gene expression modulation.

Epithalon

Developed by Russian gerontologist Vladimir Khavinson beginning in the 1980s, Epithalon (Ala-Glu-Asp-Gly) was synthesized as an analog of Epithalamin, a pineal gland extract. Research focused on telomerase activation and longevity, conducted primarily within the Russian scientific establishment.

Technological Enablers

Several technological advances enabled the peptide discoveries described above:

• Radioimmunoassay (1960s): Enabled detection of peptides at picomolar concentrations
• Solid-phase peptide synthesis (1963): Made systematic peptide synthesis practical
• Recombinant DNA technology (1970s): Enabled large-scale biosynthetic production
• Mass spectrometry advances (1980s–2000s): Improved peptide identification and quality control. See Purity and Testing
• Peptide engineering techniques (2000s–present): Fatty acid acylation, PEGylation, stapling, cyclization, and non-natural amino acid incorporation extended the pharmacological possibilities of peptides
• AI-driven design (2020s): Machine learning accelerated peptide discovery and optimization. See Future of Peptide Therapeutics

The Current Landscape

As of the mid-2020s, the peptide therapeutics field is characterized by:

• Over 80 FDA-approved peptide drugs
• Approximately 170 peptides in active clinical trials
• A global peptide therapeutics market valued in the tens of billions of dollars, driven primarily by GLP-1 agonists
• Growing convergence between peptide and small molecule drug design through technologies like stapled peptides and macrocycles
• Increasing regulatory attention to the compounding pharmacy sector and research peptide market

The trajectory from Banting and Best's crude pancreatic extracts in 1921 to rationally designed, AI-optimized multi-receptor agonists represents one of the most remarkable arcs in pharmaceutical history.

Disclaimer

This article is for educational and informational purposes only. Historical events and dates are presented based on published scientific literature and may reflect ongoing scholarly debate regarding priority of discovery.